Combination of a beta-2-adrenoceptor agonists and an aminosugars and their use for the treatment immunomodulatory disorders

ABSTRACT

The invention relates to combinations of an aminosugar and a beta-2-adrenoceptor agonist, such as salbutamol, for the treatment of diseases associated with hypersensivity and inflamation, in particular hypersensivity skin diseases. The aminosugar is preferably a monosaccharide derivative.

FIELD OF THE INVENTION

The present invention relates to the combination of a beta-2adrenoceptor agonist and an aminosugar suitably formulated in the formof a chemical complex and/or a pharmaceutical composition for thesuppression and treatment of hypersensitivity and inflammatory reactionsin mammals.

BACKGROUND OF THE INVENTION

A number of drug classes are available for the treatment ofhypersensitivity and inflammatory reactions. Among these, thecorticosteroids are some of the most widely and effective drugs used.Corticosteroids primarily exert their pharmacological action bynon-selectively inhibiting the function and proliferation of differentclasses of immune cells resulting in suppression of hypersensitivity andinflammatory reactions. Unfortunately, the corticosteroids areassociated with a number of serious side effects, e.g.immuno-suppression, osteoporosis and skin atrophy.

Non-steroidal anti-inflammatory drugs are another class of drugsextensively used in the treatment of hypersensitivity and inflammatoryreactions. Also this class of drugs is associated with serious sideeffects, in particular upon long-term use.

Hypersensitivity is defined as a state of altered reactivity in whichthe body reacts with an exaggerated immune response to a substance(antigen).

Hypersensitivity reactions underlie a large number of diseases. Amongthese, allergic and autoimmune conditions are of great importance. Aclassification of hypersensitivity diseases is given in the textbookClinical Medicine (Kumar, P. and Clark, M.: “Clinical Medicine”, 3rdedition, p. 147-150, 1994, Baliliere Tindall, London). Hypersensitivitymay be classified as type I hypersensitivity reactions (IgE mediatedallergic reactions) which is known to play a significant role includeasthma, eczema (atopic dermatitis), urticaria, allergic rhinitis andanaphylaxis. Type II hypersensitivity reactions are caused by cellsurface or tissue bound antibodies (IgG and IgM) and play a significantrole in the pathogenesis of myasthenia gravis, Good-pasture's syndromeand Addisonian pernicious anaemia. Type III hypersensitivity reactions(immune complex) are caused by autoantigens or exogenous antigens, suchas certain bacteria, fungi and parasites.

Diseases in which type III hypersensitivity reactions play a significantrole include lupus erythematosus, rheumatoid arthritis andglomerulonephritis. Type IV hypersensitivity reactions (delayed) arecaused by cell or tissue bound antigens. This type of hypersensitivityplays a significant role in a number of conditions, e.g.graft-versus-host disease, leprosy, contact dermatitis and reactions dueto insect bites.

In addition cancer may be regarded as a condition associated withhypersensitivity reactions. Cancer is caused by an uncontrolledproliferation of cells that express varying degrees of fidelity to theirprecursors. These cancer cells form a malignant tumour that enlarges andmay spread to adjacent tissues or through blood and lymph systems toother parts of the body. There are numerous forms of cancer of varyingseverity. For most types of cancer there is no effective treatmenttoday.

Generally, the treatment of hypersensitivity and inflammatory diseases,including cancer, requires long-term administration. Thus, there is aneed for therapeutic agents for the treatment of hypersensitivity andinflammatory reactions, including cancer, in particular agents that havea better safety profile than presently available drugs.

Aminosugars are generally recognised as having beneficial effect oninflammatory reactions. Aminosugars are the building blocks for the invivo generation of glycosaminoglycans, formerly known asmucopolysaccharides. Glycosaminoglycans are constituents in varioustissues in numerous mammals, both vertebrates and invertebrates and assuch not likely to be associated with adverse reactions uponadministration to mammals. Important examples of glycosaminoglycans arechondroitin sulfates, keratan sulfates in connective tissue, dermatansulfates in skin tissue and hyaluronic acid in skin tissue and synovialjoint fluid.

Administration of aminosugars or glycosaminoglycans in high(pharmacological) doses to Individuals suffering from osteoarthritis hasresulted in some relief of symptoms and nowadays the use of aminosugarsas chondroprotective agents is widely recognised (Gaby A R, Naturaltreatments for osteoarthritis, Alternative medicine review, volume 4, No5, 1999, pages 330-334). For example, the use of aminosugars andglycosaminoglycans for reducing inflammation is mentioned in WO98/48816. U.S. Pat. No. 6,046,179 relates to the treatment ofinflammatory bowel diseases by colonic administration ofN-acetylglucosamine.

Sympathomimetics are drugs that partially or completely mimic theactions of noradrenaline or adrenaline. They act either directly onalpha- and/or beta-adrenoceptors or indirectly on the presynapticterminals usually by causing the release of noradrenaline.

The effects of adrenoceptor stimulation are various. Beta-2 adrenoceptoragonists are a class of drugs known to provide bronchodilation and arewidely used in the treatment of asthma. WO 95/19336 relates to phenylethanol amine ethers for use as a beta-2 adrenoceptor agonists inbronchitis, allergic bronchitis and astma bronchiale.

EP 069042 relates to drug compositions comprising a mucopolysaccharideand a drug which is scarcely soluble in water but soluble in awater-miscible organic solvent, such as salbutamol. The drug is presentas fine crystals or fine particles attached on or between the particlesof a mucopolysaccharide.

SUMMARY OF THE INVENTION

It has been found by the present investigator that a combination of abeta-2 adrenoceptor agonist and an aminosugar significantly suppresseshypersensitivity and inflammatory reactions.

Contrarily to existing therapeutic agents, such as corticosteroids ornon-steroidal anti-inflammatory drugs, the chemical complexes andcompositions according to the present invention have the advantage ofnot being likely to be associated with any serious side effects, as allof their components are known to living organisms and are acknowledgedreported as non-toxic and well-tolerated by the organism. The presentinventor puts forward the hypothesis that the very beneficialtherapeutic index exhibited by the complex and compositions comprisingsaid complex according to the invention is superior to the use of theindividual constituents of the complex, and this is due to synergisticeffects and a lower toxic load on the organism.

Such a combination is advantageously provided in the form of a chemicalcomplex comprising a beta-2 adrenoceptor agonist and an aminosugar.Obviously, the combination may also be provided in the form of apharmaceutical composition, a dietary supplement or a cosmetic. As wasfurther recognised by the present inventor, the aminosugar according tothe present invention may be an aminosugar derivative ofmonosaccharides, oligosaccarides as well as of polysaccharides. However,the aminosugar may advantageously have a molecular weight of less than5000.

Thus, the present inventor has recognised the therapeutic activity of acombination of beta-2 adrenoceptor agonist and an aminosugar, for whichreason the said combination may be regarded as an active therapeuticagent.

Accordingly, the present invention provides a chemical complex or apharmaceutical composition comprising:

-   i) a beta-2 adrenoceptor agonist; and-   ii) an aminosugar; and optionally-   iii) a pharmaceutically acceptable carrier or carrier.

The chemical complexes and pharmaceutical compositions according to theinvention may in general be utilised in the treatment of diseasesassociated with hypersensitivity and inflammatory reactions. In generalthe combination may be utilised in i) immuno-modulation, and in morespecific terms they may be utilised in ii) the treatment or preventionof hypersensitivity diseases such as atopic eczema, contact dermatitis,seborrhoeic eczema and/or psoriasis; ii) the treatment or prevention ofIgE mediated allergic reactions and conditions such as of asthma,allergic rhinitis, and/or anaphylaxis; iv) the treatment or preventionof autoimmune disorders such as of diabetes, Crohn's disease, ulcerativecolitis, rheumatoid arthritis, gout or osteoarthritis; v) thealleviation of pain; vi) the treatment or prevention of cancer.

An important aspect of the invention relates to the use of a combinationof a beta-2 adrenoceptor agonist and an aminosugar for the preparationof a product for the treatment of diseases i) to vi) as mentioned above.

Still further aspects relate independently to a method for treatingdiseases i) to vi) as mentioned above in a mammal, such as a human,comprising the administration of a combination of a beta-2 adrenoceptoragonist and an aminosugar, pharmaceutically acceptable salts thereof, ora complex comprising said combination or said salts to said mammal.

Moreover, a still further aspect of the invention relates to a processfor the preparation of a complex comprising 1) a beta-2 adrenoceptoragonist; and ii) an aminosugar, comprising the steps of:

-   i) dissolving said beta-2 adrenoceptor and said aminosugar in a    volatile solvent or a mixture of volatile solvents; and-   ii) removing said suitable solvent so as to obtain a moisture    content of at the most 5% w/w.

DETAILED DESCRIPTION OF THE INVENTION

The present inventor provides data herein indicating that a combinationof a beta-2 adrenoceptor agonist and an aminosugar significantly reducesthe inflammation in the arachidonic acid ear inflammation test in mice.This reduction of inflammation was better for the combination than foreach of the individual compounds and also far better than that obtainedby a commonly used steroid.

It is hypothesised by the present inventor that the very advantageoustherapeutic index of the combination of a beta-2 adrenoceptor agonistand an aminosugar in comparison to each of the singular components isdue to synergistic effects between the components of the compositions.Advantageously, this allows for the utility of lower dosages, while yetproviding a surprisingly good therapeutic effect.

The invention is based, at least in part, on the combined activity of anaminosugar and a beta-2 adrenoceptor agonist in comparison to eithercomponent. This combined activity allows for the use of beta-2adrenoceptor agonists that are previously not used as therapeutic agentsbecause they were too toxic in therapeutically relevant doses or becausehigh doses were required in order to achieve said effect.

According to the invention, the combination of a beta-2 adrenoceptoragonist and an aminosugar may be provided in the form of a chemicalcomplex; in the form of a composition comprising said complex andoptionally pharmaceutically acceptable excipient(s); or in the form of apharmaceutical composition comprising the combination of beta-2adrenoceptor agonist and an aminosugar.

Without being limited to a particular theory, advantageously, saidcombination is provided in the form of a chemical complex for purposesof achieving a homogeneous mixture of the two agents, which maypositively affect the resulting therapeutic effect.

Such chemical complexes are novel and provide a surprisingly effectiveanti-hypersensitivity and anti-inflammatory effect with a surprisinglygood safety profile. Thus the chemical complexes or compositions of theinvention are virtually non-toxic at active doses and yet verytherapeutically effective.

The chemical complexes or compositions of the invention providepharmacological effects upon administration to the living organism suchas immunomodulation, suppression of hypersensitivity reactions,suppression of IgE mediated allergic reactions, suppression ofautoimmune reactions, reduction of pain, and suppression of cancer.

Accordingly, the present invention relates to a chemical complexcomprising:

-   i) a beta-2 adrenoceptor agonist; and-   ii) an aminosugar.

The term “chemical complex” is intended to include the definitiondefined by IUPAC that read as follows: “A molecular entity formed byloose association involving two or more component molecular entities(ionic or uncharged), or the corresponding chemical species. The bondingbetween the components is normally weaker than in a covalent bond.”(IUPAC Compendium of Chemical Terminology 2nd Edition (1997)).

Thus, the term “chemical complex” is intended to mean any combination ofthe components provided that the molecules of each of the components aremixed and loosely associated with each other. The term “chemicalcomplex” is not intended necessarily to Implie an ionic or otherwiseassociation between the components. It does not either include covalentbonding between the components of the complex. Moreover, the term“chemical complex” does not encompass combinations wherein one or bothof the components are in the form of particles. However, a chemicalcomplex of the invention may not be 100% pure in that some of thecomponents may be present in the form of particles. That is to say thatpreferably less than 10% of each of the components are in the form ofparticles in a chemical complex. More preferably less than 5%, less than2.5% or less than 1% is in particulate matter. Thus, a composition or achemical complex according to the invention may comprise less than 10%of one of the components in the form of particulate matter.

The complexes of the invention may be prepared according to a number ofdifferent methods, which are obvious to a person skilled in the art. Thefollowing procedures are non-limiting examples of such methods:

The components of the complex, dosed in appropriate amounts to give thecorrect molar ratio between the components, are dissolved, dispersed, orsuspended in an appropriate solvent, for example water, an organicsolvent or mixtures thereof. Non-limiting examples of suitable organicsolvents are ethanol, methanol, iso-propyl alcohol, acetone, hexane,ethylacetate or mixtures thereof.

The solvent is then removed by a technique suitable for the complex, forexample but not limited to evaporation, in vacou evaporation, spraydrying, freeze-drying, fluid bed drying or spin flash drying.Alternatively, the complex may be obtained by precipitation andsubsequent centrifugation or filtering.

In the present context, the term “aminosugar” is intended to mean one ormore amino derivatives of a monosaccharide (aldoses and ketoses) and itscorresponding sugar alcohols (alditols) such as trioses, tetroses,pentoses, hexoses, heptoses and octoses. The aldose, ketose, or alditolhas one or more hydroxy groups replaced by any amino group at anyposition, including the anomeric position. An aminosugar is thus adeoxyamino derivative of an aldose, ketose, or alditol. The term is alsointended to mean polyamino sugars, wherein more than one hydroxy grouphas been replaced by an amino group (e.g. dideoxydiamino-,trideoxytriamino-derivatives).

Moreover, the term “aminosugar” is also intended to mean aminoderivatives of di-, oligo- and poly-saccharides comprising at least oneof said monosaccharides. Consequently, in the case of di-, oligo- andpoly-saccharides, the amino group may be the position of glycosidation.Suitably, in di-, oligo- and poly-saccharides, the amino group may notbe the position of glycosidation.

An amino group of an aminosugar may be alkylated, arylated or acylatedor; alternatively, present as its free amine form (NH₂). Similarly, thehydroxyl groups may be optionally protected or derivatised such asalkylated, arylated or acylated or, alternatively, present in its freehydroxyl form.

The amine of the amino sugar may exist as its quaternary ammonium saltusing organic or mineral acids, as is known to the person skilled in theart. Furthermore, other functional groups on the aminosugar may be inthe form of a salt. Similarly, prodrug derivatives of the aminosugar areanticipated by the present inventor. The prodrug form may be the resultof the derivatisation of the amino group or another functional grouppresent on the aminosugar, as is known to the person skilled in the art.

Furthermore, an aminosugar may have one or more hydroxy groups replacedby any amino group at any position and a further one or more hydroxygroups replaced by a hydrogen (a deoxy sugar), a thiol (a thiosugar), ahalogen (a deoxyhalo sugar), an anhydrosugar (a sugar preparable via anintramolecular displacement with a hydroxyl to form an oxirane oroxetane), a carbonyl group.

Furthermore, the term aminosugar is denoted to mean aminosugars asdescribed supra but optionally substituted.

The term “optionally substituted” is intended to mean the substitutionof one or more hydrogen atoms, which is substituted with another atom,chemical group or entity, termed substituents. Illustrative examples ofsubstituents include carboxyl, formyl, amino, hydroxyl, halogen, nitro,sulphono, sulphanyl, C₁₋₆-alkyl, aryl, aryloxy, aryloxycarbonyl,arylcarbonyl, heteroaryl, amino, mono- and di(C₁₋₆-alkyl)amino;carbamoyl, mono- and di(C₁₋₆-alkyl)aminocarbonyl,amino-C₁₋₆-alkyl-aminocarbonyl, mono- anddi(C₁₋₆-alkyl)amino-C₁₋₆-alkyl-aminocarbonyl, C₁₋₆-alkylcarbonylamino,cyano, guanidino, carbamido, C₁₋₆-alkanoyloxy, C₁₋₆-alkylsulphonyloxy,dihalogen-C₁₋₆-alkyl, trihalogen-C₁₋₆-alkyl, C₁₋₆-alkoxyl, oxo,C₁₋₆-carboxyl, C₁₋₆-alkoxycarbonyl, C₁₋₆-alkylcarbonyl, where aryl andheteroaryl representing substituents may be substituted 1-5 times withC₁₋₆-alkyl, C₁₋₆-alkoxy, nitro, cyano, hydroxy, amino or halogen. Ingeneral, the above substituents may be susceptible to further optionalsubstitution.

The term “halogen” includes fluorine, chlorine, bromine and iodine.

In a particularly suitable embodiment of the invention, the aminosugaris sulphated or phosphorylated at the anomeric, 2-, 3-, 4-, or6-position, typically at the 2-, 3-, or 4-position. In another suitableembodiment of the invention the aminosugar is N-acetylated.

Furthermore, a combination of suitable embodiments include theaminosugar sulphated or phosphorylated as well as in its salt formhaving Na⁺; K⁺; Mg⁺⁺; Ca⁺⁺; or NH₄ ⁺ as counter ions.

Particularly suitable aminosugars according to the invention are aminoderivates of monosaccharides selected from the group consisting ofglucosamine, galactosamine and mannosamine, derivatives and saltsthereof. Typically, the amino derivates of monosaccharides may be in theform of salts, such as the sulfate salt and hydrochloride salts, orN-acetylated, e.g. glucosamine sulfate, glucosamine hydrochloride,N-acetylglucosamine, galactosamine sulfate, galactosamine hydrochloride,N-acetylgalactosamine, mannosamine sulfate, mannosamine hydrochloride,N-acetylmannosamine, as well as other aminosugars known to the personskilled in the art.

In suitable embodiments the aminosugar is di-, oligo-, andpoly-saccharides comprising at least one or more of the mentioned aminoderivates of monosaccharides. In the embodiment wherein the aminosugaris an oligo- or polysaccharide, said oligo- or polysaccharide preferablycontain monomeric sugars including D-glucuronic acid, L-iduronic acid,D-galacturonic acid, D-galactose, and fucose, each of which may beoptionally sulfonated or O-substituted with a protective group known tothe person skilled in the art.

In a suitable embodiment of the invention, the chemical complex and thecomposition comprises more than one aminosugar.

Preferably, the aminosugar is an amino derivate of a monosaccharide asmentioned supra. In the embodiment wherein the aminosugar is oligo- andpoly-saccharides the molecular weight is preferably less than 5000Daltons, preferably less than 4000 Daltons, more preferably less than3000 Daltons.

The aminosugar component of the invention may comprise natural,synthetic or semisynthetic aminosugars and may have been chemicallymodified, while still retaining their function. Such chemicalmodifications include but are not limited to esterification, sulfation,polysulfation, acetylation and methylation.

As stated, the invention relates to the combination of an aminosugarwith a beta-2 adrenoceptor agonist. The term “beta-2 adrenoceptoragonist” is intended to mean any component with the ability to stimulatea beta-2 adrenoceptor or parts thereof. The agonistic activity of acompound towards beta-2 adrenoceptor may be investigated by methodsknown to the person skilled in the art; eventually using salmeterol asreference.

Preferably, the beta-2 adrenoceptor agonist may be any that possess atleast 10% of the activity of salmeterol in a suitable test for beta-2adrenoceptor agonism. Preferably, the beta-2 adrenoceptor agonist has atleast 20%, more preferably at least 40% such as at least 50%, 60%, 75%,80%, 85%, 90% of the activity of salmeterol in a suitable test forbeta-2 adrenoceptor agonism.

The beta-2 adrenoceptor agonist, for illustrative purposes, may beselected from the group consisting of bambuterol, bitolterol,carbuterol, clenbuterol, clorprenaline, dioxethedrine, dopexamine,ephedrine, epinephrine, etafedrine, ethylnorepinephrine, fenoterol,formoterol, hexoprenaline, isoetarine, isoproterenol, mabuterol,metaproterenol, methoxyphenamine, pirbuterol, procaterol, protokylol,reproterol, rimiterol, ritodrine, salbutamol (albuterol), salmeterol,soterenol, terbutaline, tretoquinol, tulobuterol, derivatives, salts andenantiomeres thereof.

In interesting embodiments the beta-2 adrenoceptor agonist isterbutaline sulfate, salbutamol sulfate or formoterol fumaratedihydrate.

According to the invention the beta-2 adrenoceptor agonist maypreferably be in the form of the most effective single enantiomer oroptimal mixtures of enantiomers as known to a person skilled in the art.

As stated the combination of the two agents provides a surprisinglyeffective therapeutic agent for suppression of hypersensitivity andinflammatory reactions. The proper therapeutic efficacy may, in part, beadjusted by providing the two agents in suitable molar ratios or massratios.

The molar ratio between the beta-2 adrenoceptor agonist and theaminosugar may be about 1:10000 to 10000:1, preferably about 1:1000 to1000:1, such as about 1:500 to 500:1, such as 1:100 to 100:1, about 1:50to 50:1, or about 1:40 to 40:1, also about 1:30 to 30:1, such as about1:25 to 25:1, about 1:20 to 20:1, about 1:18 to 18:1, about 1:16 to16:1, about 1:14 to 14:1, or about 1:12 to 1:12, also about 1:10 to10:1, such as about 1:9 to 9:1, about 1:8 to 8:1, about 1:7 to 7:1,about 1:6 to 6:1, also from 1:5 to 5:1, such as from 1:4 to 4:1, e.g.from 1:3 to 3:1, such as from 1:2 to 2:1.

Alternatively defined, the ratio between the beta-2 adrenoceptor agonistand the aminosugar may be expressed as a mass ratio. The mass ratiobetween the beta-2 adrenoceptor agonist and the aminosugar may be about1:10000 to 10000:1, preferably about 1:1000 to 1000:1, such as about1:500 to 500:1, such as 1:100 to 100:1, about 1:50 to 50:1, or about1:40 to 40:1, also about 1:30 to 30:1, such as about 1:25 to 25:1, about1:20 to 20:1, about 1:18 to 18:1, about 1:16 to 16:1, about 1:14 to14:1, or about 1:12 to 1:12, also about 1:10 to 10:1, such as about 1:9to 9:1, about 1:8 to 8:1, about 1:7 to 7:1, about 1:6 to 6:1, also from1:5 to 5:1, such as from 1:4 to 4:1, e.g. from 1:3 to 3:1, such as from1:2 to 2:1.

For the administration to a mammal, such as a human, the chemicalcomplex may be administered directly, eventually provided in a capsuleor the like. More convenient, the complex may be formulated into acomposition comprising the chemical complex and optionally, one or moreacceptable excipients. Alternatively, the combination of the two agentsmay also be formulated into a composition without being provided as achemical complex.

Thus, an important aspect of the present invention relates to acomposition comprising:

-   i) a beta-2 adrenoceptor agonist;-   ii) an aminosugar; and optionally-   iii) one or more acceptable excipients or carriers.

It is to be understood that the “beta-2 adrenoceptor agonist” and the“aminosugar” of the composition are as defined supra. In one embodiment,the composition comprises the combination of beta-2 adrenoceptor agonistand the aminosugar in the form of a chemical complex as defined herein.Thus, the aminosugar may be selected from the group consisting ofglucosamine, galactosamine, mannosamine, derivatives and salts thereof,e.g. wherein the aminosugar is N-acetylglucosamine,N-acetylgalactosamine or N-acetylmannosamine. A preferred compositioncomprises glucosamine sulfate, glucosamine hydrochloride and/orN-acetylglucosamine. Moreover, the molar ratio or mass ratio between thebeta-2 adrenoceptor agonist and the aminosugar in the composition may beas defined for the complex, as discussed supra.

The term “composition” is intended to mean cosmetic compositions,pharmaceutical compositions, nutritional compositions such as foodsupplements as well as compositions in the field of cosmeceuticals andneutraceuticals.

According to the invention, the above-mentioned chemical complexes orcompositions may be combined with any other therapeutically activeagents in order to strengthen, improve, potentiate, or prolong thetherapeutic actions of said complexes and said compositions. Thusaccording to the invention, the composition or complexes may furthercomprise one or more therapeutically active agents.

The compositions according to the present invention may be formulatedfor oral, topical, transdermal, or parenteral administration, preferablyoral or topical administration. In a suitable embodiment of theinvention, the compositions are used for oral administration. In anothersuitable embodiment of the invention the compositions are used fortopical administration.

The beta-2 adrenoceptor agonist and the aminosugar may together becomprised in a single formulation or may each individually be comprisedin separate formulations. The separate formulations may be administeredin a simultaneous or non-simultaneous manner. As stated, the beta-2adrenoceptor agonist and the aminosugar are together comprised in asingle formulation.

The active ingredients of the chemical complex or pharmaceuticalcomposition of the present invention need not be administered as onepharmaceutical entity, but may of course be administered as individualcompounds or pharmaceutical compositions.

In addition to the formulations described previously, the compositionsof the invention may also be formulated as a depot preparation. Suchlong acting formulations may be administered by implantation (forexample subcutaneously or intramuscularly) or by Intramuscularinjection. Thus, for example, the compositions may be formulated withsuitable polymeric or hydrophobic materials (for example as an emulsionin an acceptable oil) or ion exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt.

The pharmaceutical compositions for oral, topical, transdermal, orparenteral administration may be in form of, e.g., solid, semisolid orfluid compositions and formulated according to conventionalpharmaceutical practice, see, e.g., “Remington: The science and practiceof pharmacy” 20^(th) ed. Mack Publishing, Easton Pa., 2000 ISBN0-912734-04-3 and “Encyclopedia of Pharmaceutical Technology”, edited bySwarbrick, J. & J. C. Boylan, Marcel Dekker, inc., New York, 1988 ISBN0-8247-2800-9.

The choice of pharmaceutically acceptable excipients in a compositionfor use according to the invention and the optimum concentration thereofis determined on the basis of the selection of the beta-2 adrenoceptoragonist, selection of the aminosugar, the kind of dosage form chosen andthe mode of administration. However, a person skilled in the art ofpharmaceutical formulation may find guidance in e.g., “Remington: Thescience and practice of pharmacy” 20^(th) ed. Mack Publishing, EastonPa., 2000 ISBN 0-912734-04-3. A pharmaceutically acceptable excipient isa substance, which is substantially harmless to the individual to whichthe composition will be administered. Such an excipient suitably fulfilsthe requirements given by the national drug agencies. Officialpharmacopeias—such as the British Pharmacopeia, the United States ofAmerica Pharmacopeia and the European Pharmacopeia set standards forwell-known pharmaceutically acceptable excipients.

For topical, trans-mucosal and trans-dermal compositions, such asadministration to the mucosa or the skin, the compositions for useaccording to the invention may contain conventional non-toxicpharmaceutically acceptable carriers and excipients includingmicrospheres and liposomes.

The topical, trans-mucosal and trans-dermal compositions for useaccording to the invention include an array of solid, semi-solid andfluid compositions. Compositions of particular relevance are e.g.pastes, ointments, hydrophilic ointments, creams, gels, hydrogels,solutions, emulsions, suspensions, lotions, liniments, resoriblets,suppositories, enema, pessaries, moulded pessaries, vaginal capsules,vaginal tablets, shampoos, jellies, soaps, sticks, sprays, powders,films, foams, pads, sponges (e.g. collagen sponges), pads, dressings(such as, e.g., absorbent wound dressings), drenches, bandages, plastersand transdermal delivery systems.

The pharmaceutically acceptable excipients for topical, trans-mucosaland trans-dermal compositions may include solvents, buffering agents,preservatives, humectants, chelating agents, antioxidants, stabilizers,emulsifying agents, suspending agents, gel-forming agents, ointmentbases, suppository bases, penetration enhancers, perfumes, skinprotective agents, diluents, disintegrating agents, binding agents,lubricants and wetting agents.

The oral compositions for use according to the invention include anarray of solid, semi-solid and fluid compositions. Compositions ofparticular relevance are e.g. solutions, suspensions, emulsions,uncoated tablets, immediate-release tablets, modified-release tablets,gastro-resistant tablets, orodispersible tablets, efferverscent tablets,chewable tablets, soft capsules, hard capsules, modified-releasecapsules, gastro-resistant capsules, uncoated granules, effervescentgranules, granules for the preparation of liquids for oral use, coatedgranules, gastro-resistant granules, modified-release granules, powdersfor oral adminstration and powders for the preparation of liquids fororal use.

The pharmaceutically acceptable excipients may include solvents,buffering agents, preservatives, humectants, chelating agents,antioxidants, stabilizers, emulsifying agents, suspending agents,gel-forming agents, diluents, disintegratig agents, binding agents,lubricants, coating agents and wetting agents.

Typical solvents may be selected from the group comprising water,alcohols, vegetable or marine oils (e.g. edible oils like almond oil,castor oil, cacao butter, coconut oil, corn oil, cottonseed oil, linseedoil, olive oil, palm oil, peanut oil, poppyseed oil, rapeseed oil,sesame oil, soybean oil, sunflower oil, and teaseed oil), mineral oils,fatty oils, liquid paraffin, polyethylene glycols, propylene glycols,glycerol, liquid polyalkylsiloxanes, and mixtures thereof.

Typical buffering agents may be selected from the group comprising ofcitric acid, acetic acid, tartaric acid, lactic acid, hydrogenphosphoricacid, diethylamine etc.

Typical preservatives may be selected from the group comprisingparabens, such as methyl, ethyl, propyl p-hydroxybenzoate, butylparaben,isobutylparaben, isopropylparaben, potassium sorbate, sorbic acid,benzoic acid, methyl benzoate, phenoxyethanol, bronopol, bronidox, MDMhydantoin, iodopropynyl butylcarbamate, EDTA, benzalconium chloride, andbenzylalcohol, or mixtures of preservatives.

Typical humectants may be selected from the group comprising glycerin,propylene glycol, sorbitol, lactic acid, urea, and mixtures thereof.Typical chelating agents are but not limited to sodium EDTA and citricacid. Typical antioxidants may be selected from the group comprisingbutylated hydroxy anisole (BHA), ascorbic acid and derivatives thereof,tocopherol and derivatives thereof, cysteine, and mixtures thereof.Suitable emulsifying agents may be selected from the group comprisingnaturally occurring gums, e.g. gum acacia or gum tragacanth; naturallyoccurring phosphatides, e.g. soybean lecithin; sorbitan monooleatederivatives; wool fats; wool alcohols; sorbitan esters; monoglycerides;fatty alcohols, fatty add esters (e.g. triglycerides of fatty acids);and mixtures thereof.

Suitable suspending agents may be selected from the group comprisingcelluloses and cellulose derivatives such as, e.g., carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, carrageenan, acacia gum, arabic gum,tragacanth, and mixtures thereof.

Suitable gel bases and viscosity-increasing components may be selectedfrom the group comprising liquid paraffin, polyethylene, fatty oils,colloidal silica or aluminium, zinc soaps, glycerol, propylene glycol,tragacanth, carboxyvinyl polymers, magnesium-aluminium silicates,Carbopol®, hydrophilic polymers such as, e.g. starch or cellulosederivatives such as, e.g., carboxymethylcellulose, hydroxyethylcelluloseand other cellulose derivatives, water-swellable hydrocolloids,carragenans, hyaluronates (e.g. hyaluronate gel optionally containingsodium chloride), and alginates including propylene glycol alginate.

Typical ointment bases may be selected from the group comprisingbeeswax, paraffin, cetanol, cetyl palmitate, vegetable oils, sorbitanesters of fatty acids (Span), polyethylene glycols, and condensationproducts between sorbitan esters of fatty acids and ethylene oxide, e.g.polyoxyethylene sorbitan monooleate (Tween).

Typical hydrophobic ointment bases may be selected from the groupcomprising paraffins, vegetable oils, animal fats, synthetic glycerides,waxes, lanolin, and liquid polyalkylsiloxanes. Typical hydrophilicointment bases are but not limited to solid macrogols (polyethyleneglycols).

Suitable powder components may be selected from the group comprisingalginate, collagen, lactose, powder, which is able to form a gel whenapplied to a wound (absorbs liquid/wound exudate).

Suitable diluents and disintegrating agents may be selected from thegroup comprising lactose, saccharose, emdex, calcium phosphates, calciumcarbonate, calcium sulphate, mannitol, starches and microcrystalinecellulose.

Suitable binding agents may be selected from the group comprisingsaccharose, sorbitol, gum acacia, sodium alginate, gelatine, starches,cellulose, sodium carboxymethylcellulose, methylcellulose,hydroxypropylcellulose, polyvinylpyrrolidone and polyetyleneglycol.

Typical wetting agents may be selected from the group comprising sodiumlaurylsulphate and polysorbate 80.

Suitable lubricants may be selected from the group comprising talcum,magnesium stearate, calcium stearate, silicium oxide, precirol andpolyethylenglycol.

Suitable coating agents may be selected from the group comprisinghydroxypropylcellulose, hydroxypropylmethylcellulose,polyvinylpropylidone, ethylcellulose and polymethylacrylates.

Typical suppository bases may be selected from the group comprisingoleum cacao, adeps solidus and polyethylenglycols.

The present inventor has recognised the therapeutic effect of thecomplexes and compositions of this invention, partly by observing thereduced inflammation of the arachidonic acid induced inflamed mouse earupon administering the complexes and compositions. This test model is acommonly employed method for screening and evaluation ofanti-inflammatory drugs.

Thus, in a broadly sense the chemical complexes or compositions providesan immunomodulating effect. Moreover, the inventor has recognised that anumber of diseases or conditions with similarities in the etiology ofthe inflammatory reactions that are provoked in the arachidonic acidinduced inflamed mouse ear may be effectively treated by the presentcomplexes and compositions of the invention. Such diseases andconditions relate in general to those associated with hypersensitivityreactions and inflammatory reactions. In a more specific sense, thechemical complexes or compositions of the invention provides suppressionof hypersensitivity reactions, suppression of inflammatory reactions,suppression of IgE mediated allergic reactions, suppression ofautoimmune reactions, reduction of pain, and suppression of cancer.

Correspondingly, a further aspect of the invention relates to a methodfor immunomodulation in a mammal, such as a human, comprising theadministration to said mammal an effective amount of a combination of abeta-2 adrenoceptor agonist and an aminosugar, or pharmaceuticallyacceptable salts thereof, or a chemical complex comprising a beta-2adrenoceptor agonist and an aminosugar, or pharmaceutically acceptablesalts thereof.

As used herein, the term “effective amount” relates to the effectivedose to be determined by a qualified practitioner, who may titratedosages to achieve the desired response. Factors for consideration ofdose will include potency, bioavailability, desiredpharmacokinetic/pharmacodynamic profiles, condition of treatment,patient-related factors (e.g. weight, health, age, etc.), presence ofco-administered medications (e.g., anticoagulants), time ofadministration, or other factors known to a medical practitioner.

Moreover, further aspects of the invention relates to a method for thetreatment of hypersensitivity disease or inflammation comprising theadministration of the above mentioned chemical complexes or compositionsof the invention to a mammal, preferentially a human.

As used herein, the “term treatment” relates to treatment of symptoms orprevention the relapse of symptoms in a person diagnosed with a diseaserelated to inflammation, hypersensitivity, cancer or pain.

According to the invention, the therapeutic action of the complexes orcompositions of the invention may be relevant to diseases involvinghypersensitivity reactions or inflammatory reactions. Hence, thetherapeutic action of the complexes or compositions of the invention maybe relevant to the treatment of conditions and diseases associated withhypersensitivity reactions, such as infections (viral, bacterial,fungal, parasitic), cold and flu, contact dermatitis, insect bites,allergic vasculitis, post-operative reactions, transplantation rejection(graft-versus-host disease), and so forth.

A further aspect of the invention relates to the use of a complex of theinvention for the treatment of autoimmune disorders. Correspondingly,the invention further relates to a method for the treatment orprevention of autoimmune disorders comprising the administration of thechemical complexes or compositions of the invention to a mammal,preferentially a human. Typically, the autoimmune disorders may beautoimmune hepatitis, Primary biliary cirrhosis, Primary sclerosingcholangitis, Autoimmune hemolytic anemias, Grave's disease, Myastheniagravis, Type 1 Diabetes Mellitus, inflammatory myopathies, Multiplesclerosis, Hashimoto's thyreoiditis, Autoimmune adrenalitis, Crohn'sDisease, Ulcerative Colitis, Glomerulonephritis, Progressive SystemicSclerosis (Scleroderma), Sjögren's Disease, Lupus Erythematosus, Primaryvasculitis, Rheumatoid Arthritis, Juvenile Arthritis, Mixed ConnectiveTissue Disease, Psoriasis, Pemfigus, Pemfigoid, and DermatitisHerpetiformis.

A still further aspect of the invention relates to a method for thetreatment or prevention of an IgE mediated allergic reaction orcondition comprising administration of the chemical complexes orcompositions of the invention to a mammal, preferably to a human. Thetherapeutic action may be relevant to IgE mediated allergic reactionsand conditions in general such as asthma, eczema (e.g. atopicdermatitis), urticaria, allergic rhinitis, anaphylaxis.

Moreover, the chemical complex or composition of the present inventionmay be used in a method for the treatment or prevention of any conditionassociated with pain. The applicant proposes the hypothesis that thetherapeutic action is related to immunomodulation, possibly to asuppressing effect on hypersensitivity reactions.

Still further, the chemical complexes or compositions of the inventionmay be employed for the treatment or prevention of cancer of any typeand at any stage. The present inventor puts forward the hypothesis thatthe anticancer effect is due to a combination of immunomodulating andtumour-suppressing effects of the complexes and compositions of theinvention.

A still further aspect of the invention relates to the use of acombination of a beta-2 adrenoceptor agonist and an aminosugar for thepreparation of a medicament for the Immunomodulation of a mammal, suchas a human. The immunomodulation typically results in the suppression ofhypersensitivity and suppression of inflammatory reactions. Theimmodulation may be associated with diseases and disorders selected fromthe group consisting of hypersensitivity skin disease such as atopiceczema, contact dermatitis, seborrhoeic eczema and/or psoriasis; IgEmediated allergic reactions such as asthma, allergic rhinitis oranaphylaxis; autoimmune disease such as chronic inflammatory disease,Crohn's disease, ulcerative colitis, rheumatoid arthritis, gout orosteoarthritis; pain and cancer.

Accordingly, the chemical complexes or compositions of the invention aresuitable for the treatment or prevention of diseases caused byinflammation of various tissues, such as the Inflammation of theprostate, in particular prostatitis.

A still further aspect of the invention relates to a process for thepreparation of a complex comprising i) a beta-2 adrenoceptor agonist;and ii) an aminosugar, comprising the steps of:

-   i) dissolving said beta-2 adrenoceptor and said aminosugar in a    volatile solvent or a mixture of volatile solvents; and-   ii) removing said suitable solvent so as to obtain a moisture    content of at the most 5% w/w.

In principle, a plethora of solvents and mixture of solvents can be usedin the preparation of complexes according to the invention. Suitablesolvents or mixture of solvents are those being substantially removedupon evaporation at room temperature, at elevated temperature, underatmospheric or reduced pressure, or upon spray drying or freeze-drying.Furthermore, solvents and mixture of solvents should be suitable fordissolving or at least partially dissolving said beta-2 adrenoceptor andsaid aminosugar at room temperature or optionally upon heating. In apreferred embodiment of the invention, the beta-2 adrenoceptor and saidaminosugar are fully dissolved in the suitable solvent or mixture ofsuitable solvents. Preferably, no traces of undissolved beta-2adrenoceptor and said aminosugar is present in the solution.

Thus, according to the invention the volatile solvent is selected fromthe group consisting of water, water-miscible, volatile organic solventsand mixtures thereof. Suitable water-miscible organic solvents isselected from the group consisting of methanol, ethanol, propanol,iso-propanol, butanol, iso-butanol, tert-butanol, acetone, acetic acid,acetonitrile, ethers, chloroform and dichlormethane. Further suitablesolvents relates to organic solvents capable of both dissolvinghydrophobic and hydrophilic substances, such as those organic solventsselected from the group consisting of dimethethylsulfoxide anddimethylformamids. Moreover, any other azeotrope solvents is preferred.

As stated, the process for preparation of a complex comprises removingof solvent so as to obtain a complex that is essentially dry, in solidform and in accordance with the IUPAC definition of a chemical complex.That is to say so as to form a complex with low moisture content and/orwherein the components are loosely associated at the molecular level andmixed with each other. The moisture being residues of water and/orresidues of the water miscible organic solvents. Thus, in a interestingembodiment of the invention, the moisture content is at the most 3% w/w,preferably at the most about 2% w/w, more preferably at the most about10% w/w, even more preferably at the most about 0.5% w/w, mostpreferably at the most about 0.2% w/w.

EXAMPLES

The following examples describe the preparation of chemical complexes ofthe present invention.

General Method Example 1-164

The beta-2 adrenoceptor agonist and the aminosugar derivative aredissolved in as little solvent as possible. The solvent is removed byspray drying or freeze-drying. After the solvent is removed the complexis a white to yellowish powder.

The solvent is water:ethanol in any v/v % combination.

The complex is suitable for any type of product e.g. pharmaceuticalproducts, dietary supplements and cosmetic formulations. Non-limitingexamples of such products are tablets, capsules, ointments and lotionsas described above.

Example 1 to 32 Molar Ratio Beta-2 Adrenoceptor Agonist/AminosugarDerivative 1:10000 (mol/mol)

beta-2 adrenoceptor agonist 1 mol Aminosugar 10000 mol Example 1.Salbutamol Glucosamine Example 2. Bambuterol Glucosamine HCl Example 3.bitolterol Glucosamine sulfate Example 4. Carbuterol Glucosamine 2sulfate, free acid Example 5. Clenbuterol Glucosamine 2 sulfate, Na⁺salt Example 6. Clorprenaline Glucosamine 2 sulfate, K⁺ salt Example 7.Dioxethedrine N-acetylglucosamine 3,4,6 sulfate, tri Na^(+ salt) Example8. Dopexamine Galactosamine 3,6 sulfate, K⁺ salt Example 9. EphedrineN-acetylgalactosamine Example 10. Epinephrine N-acetylgalactosaminesulfate Example 11. Etafedrine N-acetylglucosamine Example 12.Ethylnorepinephrine Glucosamine 6 sulfate, Na⁺ salt Example 13.Fenoterol Glucosamine 3 sulfate, Na⁺ salt Example 14. FormoterolGalactosamine 3,6 sulfate, K⁺ salt Example 15. HexoprenalineN-acetylgalactosamine Example 16. Isoetarine Glucosamine HCl Example 17.Isoproterenol Mannosamine HCl Example 18. Mabuterol N-acetylmannosamineExample 19. Metaproterenol Glucosamine sulfate Example 20.Methoxyphenamine N-acetylglucosamin Example 21. PirbuterolN-acetylgalactosamine Example 22. Procaterol N-acetylgalactosaminesulfate Example 23. Protokylol N-acetylglucosamine Example 24.Reproterol Glucosamine 6 sulfate, Na⁺ salt Example 25. RimiterolGlucosamine 3 sulfate, Na⁺ salt Example 26. Ritodrine Galactosamine 3,6sulfate, K⁺ salt Example 27. Salbutamol N-acetylgalactosamine Example28. Salmetrol Glucosamine HCl Example 29. Soterenol Mannosamine HClExample 30. Terbutaline N-acetylmannosamine Example 31. TretoquinolGlucosamine sulfate Example 32. tulobuterol N-acetylglucosamin

Example 33 to 51 Molar Ratio Beta-2 Adrenoceptor Agonist/AminosugarDerivative 1:6496 (mol/mol)

Beta-2 adrenoceptor agonist 1 mol Aminosugar 6332 mol Example 33.formoterol fumerate Glucosamine HCl dihydrate Example 34. bambuterol HClGlucosamine 3 sulfate, Na⁺ salt Example 35. Bitoltrol mesylateGalactosamine 3,6 sulfate, K⁺ salt Example 36. Clenbuterol HClN-acetylgalactosamine Example 37. Chlorprenaline HCl, H₂ON-acetylglucosamine Example 38. Dopexamine 2HCl Glucosamine sulfateExample 39. Isoetarine Glucosamine HCl Example 40. IsoproterenolMannosamine HCl Example 41. Mabuterol HCl N-acetylmannosamine Example42. Metaproterenol Glucosamine sulfate Example 43. Methoxyphenamine HClN-acetylglucosamin Example 44. Pirbuterol monoacetateN-acetylgalactosamine Example 45. Procaterol N-acetylgalactosaminesulfate Example 46. Protokylol N-acetylglucosamine Example 47.Reproterol HCl Glucosamine 6 sulfate, Na⁺ salt Example 48. Rimiterol HBrGlucosamine 3 sulfate, Na⁺ salt Example 49. Ritodrine HCl Galactosamine3,6 sulfate, K⁺ salt Example 50. Salbutamol sulfateN-acetylgalactosamine Example 51. Salmetrol Glucosamine HCl

Example 52 to 73 Molar Ratio Beta-2 Adrenoceptor Agonist/AminosugarDerivative 1:832 (mol/mol)

Beta-2 adrenoceptor agonist 1 mol Aminosugar 1500 mol Example 52.Soterenol N-acetylgalactosamine Example 53. Terbutaline Glucosamine HClExample 54. Tretoquinol HCl Glucosamine 6 sulfate, free acid Example 55.Tulobuterol Glucosamine sulfate Example 56. Salbutamol sulfateGlucosamine HCl Example 57. Formoterol Glucosamin 3 sulfate, K⁺ saltfumerate dihydrate Example 58. Dopexamine Galactosamine 3,6 sulfate, K⁺salt Example 59. Ephedrine N-acetylgalactosamine Example 60. EpinephrineN-acetylgalactosamine sulfate Example 61. Etafedrine N-acetylglucosamineExample 62. Ethylnorepinephrine Glucosamine 6 sulfate, Na⁺ salt Example63. Fenoterol HBr Glucosamine 3 sulfate, Na⁺ salt Example 64. FormoterolGalactosamine 3,6 sulfate, K⁺ salt Example 65. Isoproterenol MannosamineHCl sulfate dihydrate Example 66. Mabuterol N-acetylmannosamine Example67. Metaproterenol HCl Glucosamine sulfate Example 68. MethoxyphenamineN-acetylglucosamin Example 69. Salbutamol N-acetylgalactosamine Example70. Salmeterol Glucosamine HCl Example 71. Soterenol Mannosamine HClExample 72. Terbutaline sulfate N-acetylmannosamine Example 73.Tretoquinol Glucosamine sulfate

Example 74 to 91 Molar Ratio Beta-2 Adrenoceptor Agonist/AminosugarDerivative 1:405 (mol/mol)

Beta-2 adrenoceptor agonist 1 mol Aminosugar 405 mol Example 74.Salbutamol N-acetylglucosamin Example 75. bitolterol GalactosamineExample 76. Carbuterol Glucosamine HCl Example 77. Clenbuterol HClGlucosamine sulfate Example 78. Clorprenaline Galactosamine 3,6 sulfate,di Na^(+salt) Example 79. Dioxethedrine N-acetylglucosamin HCl Example80. Ethylnorepinephrine HCl Glucosamine 6 sulfate, Na⁺ salt Example 81.Fenoterol Glucosamine 3 sulfate, Na⁺ salt Example 82. FormoterolGalactosamine 3,6 sulfate, K⁺ salt Example 83. Isoproterenol MannosamineHCl Example 84. Mabuterol HCl N-acetylmannosamine Example 85.Metaproterenol HCl Glucosamine sulfate Example 86. MethoxyphenamineN-acetylglucosamin Example 87. Salbutamol sulfate N-acetylgalactosamineExample 88. Salmetrol Glucosamine HCl Example 89. Soterenol HClMannosamine HCl Example 90. Terbutaline sulfate N-acetylmannosamineExample 91. Tretoquinol Glucosamine sulfate

Example 92 to 115 Molar Ratio Beta-2 Adrenoceptor Agonist/AminosugarDerivative 1:130 (mol/mol)

Beta-2 adrenoceptor agonist 1 mol Aminosugar 130 mol Example 92.Salbutamol Glucosamine sulfate Example 93. Clenbuterol GalactosamineExample 94. Clorprenaline N-acetylgalactosamine 3,6 sulfate, K⁺ saltExample 95. Dioxethedrine Glucosamine sulfate Example 96. DopexamineN-acetylglucosamine HCl Example 97. Ephedrine N-acetylglucosamine 3sulfate, free acid Example 98. Epinephrine Galactosamine 4 sulfate, K⁺salt Example 99. Etafedrine N-acetylgalactosamine 3,6 sulfate, Na⁺ saltExample 100. Ethylnorepinephrine Glucosamine 6 sulfate, K⁺ salt Example101. Fenoterol Glucosamine 2,3 sulfate, di Na⁺ salt Example 102.Formoterol fumerate N-acetylglucosamine HCl dihydrate Example 103.Hexoprenaline Glucosamine sulfate Example 104. Salmetrol Glucosamine HClExample 105. Soterenol Mannosamine HCl Example 106. TerbutalineN-acetylmannosamine Example 107. Tretoquinol Glucosamine sulfate Example108. Hexoprenaline N-acetylgalactosamine Example 109. IsoetarineGlucosamine HCl Example 110. Isoproterenol Mannosamine HCl Example 111.Mabuterol N-acetylmannosamine Example 112. Metaproterenol Glucosaminesulfate Example 113. Methoxyphenamine N-acetylglucosamin Example 114.Pirbuterol N-acetylgalactosamine Example 115. ProcaterolN-acetylgalactosamine sulfate

Example 116 to 124 Molar Ratio Beta-2 Adrenoceptor Agonist/AminosugarDerivative 1:19 (mol/mol)

Beta-2 adrenoceptor agonist 1 mol Aminosugar 19 mol Example 116.Salbutamol Glucosamine sulfate Example 117. Salbutamol sulfateGlucosamine 2 sulfate, K⁺ salt Example 118. Bitolterol GalactosamineExample 119. Carbuterol Glucosamine Example 120. ClenbuterolN-acetylgalactosamine 4 sulfate, K⁺ salt Example 121. ClorprenalineN-acetyl-glucosamine HCl Example 122. Tretoquinol Galactosamine 2sulfate, Na⁺ salt Example 123. Hexoprenaline Mannosamine HCl Example124. Isoetarine N-acetylmannosamine

Example 125 to 137 Molar Ratio Beta-2 Adrenoceptor Agonist/AminosugarDerivative 1:1 (mol/mol)

Beta-2 adrenoceptor agonist 1 mol Aminosugar 1 mol Example 125.Bambuterol HCl Glucosamine HCl Example 126. Bitolterol mesylateN-acetyl-glucosamine Example 127. Salbutamol Galactosamine sulfateExample 128. Formoterol fumerate Glucosamine 3,4,6 sulfate, freedihydrate acid Example 129. Tretoqulnol HCl N-acetylgalactosamine HClExample 130. Hexoprenaline sulfate N-acetylgalactosamine Example 131.Broxaterol Glucosamine HCl Example 132. Isoproterenol Mannosamine HClExample 133. Mabuterol N-acetylmannosamine Example 134. Metaproterenolsulfate Glucosamine sulfate Example 135. MethoxyphenamineN-acetylglucosamin Example 136. Pirbuterol 2HCl N-acetylgalactosamineExample 137. Procaterol N-acetylgalactosamine sulfate

Example 138 to 143 Molar Ratio Beta-2 Adrenoceptor Agonist/AminosugarDerivative 5:1 (mol/mol)

Beta-2 adrenoceptor agonist 5 mol Aminosugar 1 mol Example 138.Salbutamol Galactosamine 4 sulfate, K⁺ salt Example 139. Formoterolfumerate N-acetylglucosamin dihydrate Example 140. Fenoterol HBrN-acetylgalactosamine Example 141. Mabuterol HCl Mannosamine Example142. Methoxyphenamine N-acetylglucosamine HCl HCl Example 143.Reproterol Glucosamine sulfate

Example 144 to 148 Molar Ratio Beta-2 Adrenoceptor Agonist/AminosugarDerivative 50:1 (mol/mol)

Beta-2 adrenoceptor agonist 50 mol Aminosugar 1 mol Example 144.Dioxethedrine Glucosamine sulfate Example 145. Dopexamine 2HClN-acetylglucosamine Example 146. Ephedrine HCl Galactosamine HCl Example147. Epinephrine N-acetylmannosamine Example 148. Salbutamol sulfateN-acetylglucosamin HCl

Example 149 to 153 Molar Ratio Beta-2 Adrenoceptor Agonist/AminosugarDerivative (mol/mol)

Beta-2 adrenoceptor agonist 500 mol Aminosugar 1 mol Example 149.Rimiterol Glucosamine sulfate Example 150. Bitolterol mesylateN-acetylglucosamine Example 151. Salbutamol Galactosamine HCl Example152. Salmetrol xinafoate Mannosamine Example 153. Clenbuterol HClN-acetylglucosamin HCl

Example 154 to 159 Molar Ratio Beta-2 Adrenoceptor Agonist/AminosugarDerivative 1000:1 (mol/mol)

Beta-2 adrenoceptor agonist 1000 mol Aminosugar 1 mol Example 154.Mabuterol HCl Glucosamine sulfate Example 155. ClenbuterolN-acetylglucosamine Example 156. Salbutamol sulfate Galactosamine HClExample 157. Tulobuterol HCl N-acetylgalactosamine 3,6 sulfate, dl Na⁺salt Example 158. Ritodrine HCl N-acetylglucosamin HCl Example 159.Protokylol Mannosamine HCl

Example 160 to 164 Molar Ratio Beta-2 Adrenoceptor Agonist/AminosugarDerivative 10000:1 (mol/mol)

Beta-2 adrenoceptor agonist 10000 mol Aminosugar 1 mol Example 160.Pirbuterol 2HCl Glucosamine sulfate Example 161. MethoxyphenamineN-acetylglucosamine Example 162. salbutamol Galactosamine HCl Example163. Isoetarine N-acetylgalactosamine 3,6 sulfate, dl Na⁺ salt Example164. Fenoterol HCl N-acetylglucosamin HCl

General Method Example 165-176

A quantity of the beta-2 adrenoceptor agonist and the aminosugarderivative are transferred to a hard gelatine capsule.

Example 165 to 170 Capsule 500 mg, Molar Ratio Beta-2 AdrenoceptorAgonist/Aminosugar Derivative 1:1000 (mol/mol)

Beta-2 adrenoceptor agonist 1 mol Aminosugar 1000 mol Example 165.Salbutamol 239.31 g/mol Glucosamin HCl 0.55 mg 215.6 g/mol 499.45 mgExample 166. Salbutamol sulfate 576.7 g/mol N-acetylglucosamine 1.3 mg221.2 g/mol. 498.7 mg Example 167. Formoterol fumerate Glucosaminesulfate dihydrate 840.91 g/mol 605.1 g/mol 499.3 mg 0.7 mg Example 168.Formoterol 344.41 g/mol Galactosamine HCl 0.8 mg 215.6 g/mol 499.2 mgExample 169. Fenoterol 303.36 g/mol Mannosamine HCl 0.7 mg 215.6 g/mol499.3 mg Example 170. Mabuterol 310.75 g/mol N-acetylmannosamine 0.7 mg221.2 g/mol 499.3 mg

Example 171 to 176 Capsule 750 mg, Molar Ratio Beta-2 AdrenoceptorAgonist/Aminosugar Derivative 1:53(mol/mol).

Beta-2 adrenoceptor agonist 1 mol Aminosugar 53 mol Example 171.Dopexamine 356.51 g/mol Glucosamin HCl 22.7 mg 215.6 g/mol 727.3 mgExample 172. Salbutamol sulfate 576.7 g/mol N-acetylglucosamine 35.16 mg221.2 g/mol 714.84 mg Example 173. Formoterol fumerate dihydrateGlucosamine sulfate 840.91 g/mol 605.1 g/mol 19.16 mg 730.84 mg Example174. Salbutamol 239.31 g/mol N-acetylglucosamine 15.0 mg 221.2 g/mol735.0 mg Example 175. Ephedrine 165.24 g/mol N-acetylmannosamine 10.4 mg221.2 g/mol 739.6 mg Example 176. Formoterol 344.41 g/mol Glucosamin HCl21.94 mg 215.6 g/mol 728.06 mg

Example 177

Objective

The objective of this study is to assess the effect of three doses oftwo chemical complexes of the invention systemically administered in thearachidonic acid induced ear inflammation test in the mouse, a commonlyemployed method for screening and evaluation of antiinflammatory drugs.Dexamethasone was employed as reference compound.

Test Articles and Vehicle

The test articles are the complexes of the invention prepared accordingto example 33 and example 92 (Compound 33 and Compound 92 in thefollowing). Compound 33, Compound 92 and dexamethasone are obtained fromAstion A/S, Denmark.

Animals

The study was performed in female BALB/ca mice from M & B A/S, DK-8680Ry. At start of the acclimatisation period the mice were in the weightrange of 20 g (+/−5 g).

Housing

The study took place in an animal room provided with filtered air. Thetemperature in the room was set at 21-23° C. and the relative humidityto ≧30%. The room was illuminated to give a cycle of 12 hours light and12 hours darkness. Light was on from 06.00 till 18.00 h.

The animals were housed in Macrolon type III cages (40×25×14 cm), 10 ineach cage. The cages were cleaned and the bedding changed at least oncea week.

Beddinq

The bedding was sawdust (Tapvel 4HV) from Tapvel Oy, 73620 Kortteinen,Finland.

Diet

A complete pelleted rodent diet “Altromin 1324” from Chr. Petersen,DK-4100 Ringsted, was available ad libitum.

Drinking Water

The animals had free access to bottles with domestic quality drinkingwater. The drinking water was changed daily.

Animal Randomisation and Allocation

On the day of arrival the animals were randomly allocated to groups of 8mice.

Body Weight

The animals were weighed on the day of dosing.

Procedure

The test substances and reference compound were administeredintraperitoneally in volumes of 20 ml per kg body weight 30 minutesbefore application of arachidonic acid to the ear.

All groups were treated with 20 μl arachidonic acid, 100 mg/ml inacetone, on the right ear.

The doses were as follows: Drug Dose, mg/kg Vehicle, PBS —, i.p.Compound 92 1000 mg/kg, i.p. Compound 92  300 mg/kg, i.p. Compound 92 100 mg/kg, i.p. Compound 33 1000 mg/kg, i.p. Compound 33  300 mg/kg,i.p. Compound 33  100 mg/kg, i.p. Dexamethasone   6 mg/kg, i.p.Dexamethasone   2 mg/kg, i.p.

One hour after the arachidonic acid application the mice weresacrificed, the ears cut from the tip with a punch biopsy knife (8 mmdiameter) and weighed.

Mean weights and standard deviations were calculated. Relative earoedema was assessed as the weight difference between right and left earof each mouse expressed as percent of the left ear. Percent inhibitionof the relative ear oedema compared with the vehicle treated groups wascalculated for the test substance and reference compound treated groups.

Clinical Signs

All visible signs of ill health and any behavioural changes wererecorded daily during the study. Any deviation from normal was recordedwith respect to time of onset, duration and intensity.

Statistics

Differences in relative ear oedema between the vehicle treated groupsand the test substance and reference compound treated groups were testedfor significance employing a non-parametric statistical method ofanalysis, the Mann-Whitney U test. The required level of significancewas p<0.05.

All statistical analysis was performed employing the statisticalsoftware package Analyse-it v. 1.62.

Results

Clinical Signs

Arachidonic add caused an inflammation in the right ears, which wasvisible after about 30 minutes. It could clearly be observed that theright ears were bright red and the left ears pale. The test articles tosome extent prevented the reaction in the right ear. No test substancerelated adverse reactions were observed.

Ear Oedema

The various concentrations of the test articles inhibited the relativeoedema as shown in the table below: % Inhibition Dose, mg per ofrelative Drug application ear oedema Mann-Whitney U test Vehicle, PBS —,i.p. — — Compound 92 1000 mg/kg, i.p. 65 p < 0.0001 Compound 92  300mg/kg, i.p. 44 p = 0.0009 Compound 92  100 mg/kg, i.p. 14 p = 0.0652Compound 33 1000 mg/kg, i.p. 79 p = 0.0002 Compound 33  300 mg/kg, i.p.64 p < 0.0001 Compound 33  100 mg/kg, i.p. 47 p = 0.0052 Dexamethasone  6 mg/kg, i.p. 0 p = 0.8359 Dexamethasone   2 mg/kg, i.p. 0 p = 0.6008

Compound 92 and Compound 33 yielded a dose dependent and at all dosesstatistically significant inhibition of ear oedema. Dexamethasone, thereference compound, surprisingly did not inhibit ear oedema. This isattributed to a slower onset of action. Thus, the data imply thatCompound 92 and Compound 33 have a faster onset of action thandexamethasone.

Conclusion

The data imply that systemically administered Compound 92 and Compound33 are potent Inhibitors of arachidonic acid induced ear oedema, with afaster onset of action than dexamethasone.

Example 178

Objective

The objective of this study is to assess the effect of a dose of acomplex according to compared to the effect of the corresponding dosesof the components of the complex. All compounds were systemicallyadministered in the arachidonic acid induced ear inflammation test inthe mouse, a commonly employed method for screening and evaluation ofantiinflammatory drugs. Methylprednisolone was employed as referencecompound.

Test Articles and Vehicle

The test articles are the complex of the invention prepared according toexample 92 (Compound 92 in the following) and its components salbutamoland glucosamine sulfate. The substances were obtained from Astion A/S,Denmark.

Animals

The study was performed in female BALB/ca mice from M & B A/S, DK-8680Ry. At start of the acclimatisation period the mice were in the weightrange of 20 g (+/−5 g).

Housing

The study took place in an animal room provided with filtered air. Thetemperature in the room was set at 21-23° C. and the relative humidityto ≧30%. The room was illuminated to give a cycle of 12 hours light and12 hours darkness. Light was on from 06.00 till 18.00 h.

The animals were housed in Macrolon type III cages (40×25×14 cm), 10 ineach cage. The cages were cleaned and the bedding changed at least oncea week.

Bedding

The bedding was sawdust (Tapvel 4HV) from Tapvel Oy, 73620 Kortteinen,Finland.

Diet

A complete pelleted rodent diet “Altromin 1324” from Chr. Petersen,DK-4100 Ringsted, was available ad libitum.

Drinking Water

The animals had free access to bottles with domestic quality drinkingwater. The drinking water was changed daily.

Animal Randomisation and Allocation

On the day of arrival the animals were randomly allocated to groups of10 mice.

Body Weight

The animals were weighed on the day of dosing and termination of thestudy.

Procedure

The test substances and reference compound were administeredintraperitoneally in volumes of 20 ml per kg body weight 30 minutesbefore application of arachidonic acid to the ear.

All groups were treated with 20 μl arachidonic acid, 100 mg/ml inacetone, on the right ear.

The doses were as follows: Drug Dose, mg/kg Vehicle, PBS —, i.p.Compound 92  1000 mg/kg, i.p. Glucosamine sulfate   997 mg/kg, i.p.Salbutamol  3.0 mg/kg, i.p. Methylprednisolone   30 mg/kg, i.p.

One hour after the arachidonic acid application the mice weresacrificed, the ears cut from the tip with a punch biopsy knife (8 mmdiameter) and weighed.

Mean weights and standard deviations were calculated. Relative earoedema was assessed as the weight difference between right and left earof each mouse expressed as percent of the left ear. Percent inhibitionof the relative ear oedema compared with the vehicle treated groups wascalculated for the test substance and reference compound treated groups.

Clinical Signs

All visible signs of ill health and any behavioural changes wererecorded daily during the study. Any deviation from normal was recordedwith respect to time of onset, duration and intensity.

Statistics

Differences in relative ear oedema between the vehicle treated group andthe other groups were tested for significance employing a non-parametricstatistical method of analysis, the Mann-Whitney U test. The requiredlevel of significance will be p<0.05. Similarly, the difference betweenthe compound 92 treated group and the groups treated with thecorresponding amounts of salbutamol and glucosamine sulfaterespectively, were tested for significance to establish whether Compound92 displays a significantly better effect than its components at thedose they occur in Compound 92. All statistical analysis was performedemploying the statistical software package Analyse-it v. 1.62.

Results

Clinical Signs

Arachidonic acid caused an inflammation in the right ears, which wasvisible after about 30 minutes. It could clearly be observed that theright ears were bright red and the left ears pale. The test articles tosome extent prevented the reaction in the right ear. No test substancerelated adverse reactions were observed.

Ear Oedema

The various concentrations of the test articles inhibited the relativeoedema as shown in the table below: % Inhibition of relative earMann-Whitney U Drug Dose, mg/kg oedema test Vehicle, PBS — — — Compound92  1000 mg/kg 73 p < 0.0001 Glucosamine sulfate   997 mg/kg 9 p =0.1399 Salbutamol  3.0 mg/kg 55 p < 0.0001 Methylprednisolone   30 mg/kg55 p < 0.0001

Compound 92 yielded a statistically significant inhibition of earoedema. Glucosamine sulfate inhibited ear oedema mildly, and notstatistically significantly, while Salbutamol inhibited ear oedemasignificantly. In the group receiving Compound 92 the relative earoedema was 71% and 40% lower than in the groups receiving thecorresponding doses of glucosamine sulfate and salbutamol, respectively.These differences were statistically significant, p<0.0001 and p=0.0076,respectively, and since Compound 92 reached a higher level of inhibitionthan the sum of inhibition of the corresponding doses of glucosaminesulfate and salbutamol, the data imply a synergistic effect.

Compound 92 yielded a 41% lower ear oedema than methylprednisolone andthis difference was significant (p=0.0021).

Conclusion

The data imply that systemically administered Compound 92 is a potentinhibitor of arachidonic acid induced ear oedema and that thesurprisingly strong inhibition is obtained through a synergistic effectbetween the components of the complex.

Example 179

A woman (70 years old) had been suffering from significant muscular painfor 6 years and had for periods been under treatment with differentanalgesics including ibuprofen and celecoxib with limited success. Thelast year she had continuously been taking a supplement of glucosaminesulfate, 1500 mg a day, but only obtained a small improvement of hersymptoms. She was then treated with the complex of the inventiondisclosed in example 56 (1500 mg/day) instead of glucosamine sulfate.After two days she could feel a significant improvement compared totaking the aminosugar alone. After two weeks she was symptom free forthe first time in 6 years, which persisted for another 6 weeks oftreatment, where after the treatment was terminated. No adverse effectswere observed.

Example 180

A male, 68 years had been suffering from osteoarthritis of the knees for8 years and had for periods been under treatment with differentanalgesics including diclofenac codeine and rofecoxib with limitedsuccess. He had also tried the recommended dose of glucosamine indifferent formulations, but with very limited effect. He was thentreated with the complex of the invention disclosed in example 56 (1500mg/day). After four days he experienced a significant improvement of hismajor symptom pain in the knees in relation to walking. The improvementcontinued and after two weeks he was completely symptom free. Theimprovement persisted for the entire treatment period of 10 weeks, whereafter the treatment was terminated. No adverse effects were observed.

1-53. (canceled)
 54. A chemical complex comprising: i) a beta-2adrenoceptor agonist; and ii) an aminosugar selected from the groupconsisting of glucosamine, mannosamine, salts and derivatives thereof,wherein the derivatives thereof is selected from the group consisting ofderivatives wherein the amino group and/or hydroxyl group of theaminosugar is alkylated, arylated or acylated, and wherein the anomeric,2-, 3-, 4-, or 6-position is sulphated or phosphorylated.
 55. A chemicalcomplex according to claim 54, wherein the beta-2 adrenoceptor agonistis selected from the group consisting of bambuterol, bitolterol,broxaterol, carbuterol, clenbuterol, clorprenaline, dioxethedrine,dopexamine, ephedrine, epinephrine, etafedrine, ethylnorepinephrine,fenoterol, formoterol, hexoprenaline, isoetarine, isoproterenol,mabuterol, metaproterenol, methoxyphenamine orciprenaline, pirbuterol,procaterol, protokylol, reproterol, rimiterol, ritodrine, salbutamol(albuterol), salmeterol, soterenol, terbutaline, tretoquinol,tulobuterol, derivatives and salts thereof.
 56. The chemical complexaccording to claim 54, wherein the aminosugar is glucosaminehydrochloride or glucosamine sulfate.
 57. The chemical complex accordingto claim 54, wherein the beta-2 adrenoceptor agonist is salbutamolsulfate, terbutaline sulfate or formoterol fumarate dihydrate.
 58. Acomposition comprising: i) a beta-2 adrenoceptor agonist; ii) anaminosugar selected from the group consisting of glucosamine,mannosamine, salts and derivatives thereof, wherein the derivativesthereof is selected from the group consisting of wherein the amino groupand/or hydroxyl group of the aminosugar is alkylated, arylated oracylated, and wherein the anomeric, 2-, 3-, 4-, or 6-position issulphated or phosphorylated; and iii) one or more acceptable excipientsor carriers.
 59. The composition according to claim 58, wherein thebeta-2 adrenoceptor agonist is selected from the group consisting ofbambuterol, bitolterol, carbuterol, clenbuterol, clorprenaline,dioxethedrine, dopexamine, ephedrine, epinephrine, etafedrine,ethylnorepinephrine, fenoterol, formoterol, hexoprenaline, isoetarine,isoproterenol, mabuterol, metaproterenol, methoxyphenamine, pirbuterol,procaterol, protokylol, reproterol, rimiterol, ritodrine, salbutamol(albuterol), salmeterol, soterenol, terbutaline, tretoquinol,tulobuterol, derivatives and salts thereof.
 60. The compositionaccording to claim 58, wherein the aminosugar is glucosaminehydrochloride or glucosamine sulfate.
 61. The composition according toclaim 58, wherein the beta-2 adrenoceptor agonist is salbutamol sulfate,terbutaline sulfate or formoterol fumarate dihydrate.
 62. Thecomposition according to claim 58, wherein the beta-2 adrenoceptoragonist and the aminosugar is in the form of a chemical complexcomprising: i) a beta-2 adrenoceptor agonist; and ii) an aminosugarselected from the group consisting of glucosamine, mannosamine, saltsand derivatives thereof, wherein the derivatives thereof is selectedfrom the group consisting of derivatives wherein the amino group and/orhydroxyl group of the aminosugar is alkylated, arylated or acylated, andwherein the anomeric, 2-, 3-, 4-, or 6-position is sulphated orphosphorylated.
 63. The composition according to claim 58, furthercomprising one or more therapeutically active agents other than a beta-2adrenoceptor agonist and the aminosugar.
 64. The composition accordingto claim 58 in a form selected from the group consisting of oralformulation, topical formulation, transdermal formulation, andparenteral formulation.
 65. A method for the suppression ofhypersensitivity and/or inflammatory reactions in a mammal, comprisingthe administration to said mammal of a combination of a beta-2adrenoceptor agonist and an aminosugar, or pharmaceutically acceptablesalts thereof, the aminosugar being selected from the group consistingof glucosamine, mannosamine, salts and derivatives thereof, wherein thederivatives thereof is selected from the group consisting of wherein theamino group and/or hydroxyl group of the aminosugar is alkylated,arylated or acylated, and wherein the anomeric, 2-, 3-, 4-, or6-position is sulphated or phosphorylated.
 66. The method according toclaim 65, for the treatment or prevention of hypersensitivity skindisease in a mammal.
 67. The method according to claim 66, for thetreatment or prevention of atopic eczema, contact dermatitis,seborrhoeic eczema and/or psoriasis.
 68. The method according to claim66, for the treatment or prevention of contact dermatitis or psoriasis.69. The method according to claim 65 for the treatment or prevention ofIgE mediated allergic reaction and/or condition.
 70. The methodaccording to claim 69, for the treatment or prevention of asthma,allergic rhinitis, and/or anaphylaxis.
 71. The method according to claim65 for the treatment or prevention of autoimmune disease and/or chronicinflammatory.
 72. The method according to claim 71, for the treatment ofautoimmune hepatitis, Primary biliary cirrhosis, Primary sclerosingcholangitis, Autoimmune hemolytic anemias, Grave's disease, Myastheniagravis, Type 1 Diabetes Mellitus, Inflammatory myopathies, Multiplesclerosis, Hashimoto's thyreoiditis, Autoimmune adrenalitis, Crohn'sDisease, Ulcerative Colitis, Glomerulonephritis, Progressive SystemicSclerosis (Scleroderma), Sjögren's Disease, Lupus Erythematosus, Primaryvasculitis, Rheumatoid Arthritis, Juvenile Arthritis, Mixed ConnectiveTissue Disease, Psoriasis, Pemfigus, Pemfigoid or DermatitisHerpetiformis.
 73. The method according to claim 72, for the treatmentor prevention of diabetes, Crohn's disease, ulcerative colitis,rheumatoid arthritis, multiple sclerosis, gout or osteoarthritis. 74.The method according to claim 65, wherein the mammal is a human.
 75. Themethod according to claim 65, wherein the combination of the beta-2adrenoceptor agonist and the aminosugar is a chemical complexcomprising: i) a beta-2 adrenoceptor agonist; and ii) an aminosugarselected from the group consisting of glucosamine, mannosamine, saltsand derivatives thereof, wherein the derivatives thereof is selectedfrom the group consisting of derivatives wherein the amino group and/orhydroxyl group of the aminosugar is alkylated, arylated or acylated, andwherein the anomeric, 2-, 3-, 4-, or 6-position is sulphated orphosphorylated.
 76. The method according to claim 65, wherein thecombination of a beta-2 adrenoceptor agonist and the aminosugar is acomposition comprising: i) a beta-2 adrenoceptor agonist; ii) anaminosugar selected from the group consisting of glucosamine,mannosamine, salts and derivatives thereof, wherein the derivativesthereof is selected from the group consisting of wherein the amino groupand/or hydroxyl group of the aminosugar is alkylated, arylated oracylated, and wherein the anomeric, 2-, 3-, 4-, or 6-position issulphated or phosphorylated; and iii) one or more acceptable excipientsor carriers.
 77. The method according to claim 65, wherein thecombination of a beta-2 adrenoceptor agonist and an aminosugar, orpharmaceutically acceptable salts thereof, are together comprised in asingle formulation or are each individually comprised in separateformulations.
 78. The method according to claim 65, wherein thecombination of a beta-2 adrenoceptor agonist and an aminosugar isadministered by means of oral, topical, transdermal, or parenteraladministration, or combinations thereof.
 79. The method according toclaim 77, wherein the separate formulations are administered in asimultaneous or non-simultaneous manner.
 80. The method according toclaim 65, further comprising administering one or more therapeuticallyactive substances other than the said beta-2 adrenoceptor agonist andsaid aminosugar.